Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors

Myelokathexis is a congenital disorder that causes severe chronic leukopeni a and neutropenia. Characteristic findings include degenerative changes and hypersegmentation of mature neutrophils and hyperplasia of bone marrow mye loid cells. The associated neutropenia can be partially corrected by treatm ent with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macro phage colony-stimulating factor (GM-CSF), These features led us to propose that accelerated apoptosis of neutrophil precursors might account for the n eutropenic phenotype, Blood and bone marrow aspirates were obtained from 4 patients (2 unrelated families) with myelokathexis before G-CSF therapy and from 2 of the affected persons after G-CSF therapy (1 mu g/kg per day subc utaneously for 3 weeks). Bone marrow was fractionated using immunomagnetic bead cell sorting into CD34(+), CD33(+)/CD34(-), and CD15(+)/CD34(-)/CD33(- ) cell populations. Examination of these cells by flow cytometry and electr on microscopy revealed abundant apoptosis in the CD15(+) neutrophil precurs or population, characterized by enhanced annexin-V binding, extensive membr ane blebbing, condensation of heterochromatin, and cell fragmentation. Colo ny-forming assays demonstrated significant reduction in a proportion of bon e marrow myeloid-committed progenitor cells. Immunohistochemical analysis r evealed a selective decrease in bcl-x, but not bcl-2, expression in the CD1 5(+)/CD34(-)/CD33(-) cell population com- pared with similar subpopulations of control bone marrow-derived myeloid precursors. After G-CSF therapy, ap optotic features of patients' bone marrow cells were substantially reduced, and the absolute neutrophil counts (ANC) and expression of bcl-x in CD15()/CD34(-)/CD33(-) cells increased. The authors concluded that myelokathexis is a disease characterized by the accelerated apoptosis of granulocytes an d the depressed expression of bcl-x in bone marrow-derived granulocyte prec ursor cells. These abnormalities are partially corrected by the in vivo adm inistration of G-CSF, (C) 2000 by The American Society of Hematology.